The pituitary gland is a special area of the brain that releases two hormones necessary for normal ovulation. These hormones, collectively called gonadotropins, are individually known as follicle stimulating hormone (FSH) and luteinizing hormone (LH). In the natural menstrual cycle FSH is the pituitary message that stimulates the development of egg-containing follicles in the ovaries. Each follicle contains one egg. Each follicle also contains specialized cells called granulosa cells, which produce the hormone estradiol. The estradiol secreted during the first half of a menstrual cycle stimulates growth of the uterine lining (endometrium) and production of the watery "raw egg white" cervical mucous. After approximately two weeks, the pituitary releases a surge of LH hormone, which triggers ovulation (the release of the egg) and initiates the production of progesterone by the follicle, which is now called the corpus luteum. Two weeks after ovulation, if a pregnancy has not occurred, the corpus luteum stops production of progesterone, the endometrium sloughs and menstrual bleeding occurs.

There are a number of medications used to treat infertility that contain gonadotropins, i.e. Repronex, Fertinex, Follistim and Gonal-F. The important active hormone in each of these medications is FSH.

FSH is a small protein that would be destroyed by the digestive enzymes in the stomach if taken orally. Therefore, these medications are given by injection either subcutaneously (i.e. under the skin with a very small needle) or intramuscularly (i.e. in the buttocks, especially for women with an increased body mass index). The newest medications, Fertinex, Follistim and Gonal-F can be given subcutaneously and have, therefore, become quite popular. All these medications can be used separately or in different combinations. They are not synthesized from chemicals but are purified from the urine of menopausal women (Repronex, Fertinex) or created by recombinant DNA technology (Follistim, Gonal-F). They are supplied as a powder that must be mixed with sterile water and given as a daily injection, or as pre-mixed cartridge, which fits into a self-injection device.

When these medications are administered, they augment the natural pituitary FSH to stimulate follicle growth. The primary mechanism of fertility enhancement is through the stimulation of multiple follicles (i.e. multiple eggs) by the increased blood levels of FSH. Blood tests and ultrasound exams must be performed several times during a treatment cycle to ensure that the ovaries are receiving the proper level of stimulation. Visualizing the ovaries by ultrasound allows determination of the number and size of the follicles in each ovary. Follicles are thought to contain mature eggs once their measured diameter is at least 16 mm. Blood levels of estradiol further evaluate the maturity of the eggs and should rise proportionate to follicle growth. When it is determined that the follicles should contain mature eggs, an injection of hCG (human chorionic gonadotropin - the hormone of pregnancy) is given. hCG binds to the LH receptors in the ovary, which then causes ovulation and formation of the corpus luteum to begin progesterone production. Ovulation usually occurs approximately 34 - 42 hours after the injection.

Controlled stimulation with these medications can provide several benefits.
1. They are very effective at inducing ovulation, even when other drugs such as clomid have failed.
2. Multiple eggs may be released each cycle, thus increasing the chances for fertilization and pregnancy.
3. The timing of ovulation may be more precisely predicted for more effective use of intrauterine insemination.

A gonadotropin stimulation cycle may have to be canceled for any of the following reasons:
1. Too many follicles growing
2. Estradiol levels that are too high
3. Inadequate follicle development or
4. Premature spontaneous ovulation.

There is no doubt that the expense, injections, inconvenience, rigid scheduling, and uncertainty about adequacy of response can combine to make gonadotropin treatment cycles stressful. Sometimes it will be necessary to cancel cycles for too little or too robust of a response. Although no one likes to have their cycle cancelled, the inescapable reality is that responses are unique for each individual. It can take 2 or sometimes even 3 cycles to arrive at the optimal stimulation protocol that combines safety and effectiveness.

Although many patients wish to complete their gonadotropin stimulation cycles as quickly as possible, if a cycle is unsuccessful, the following cycle may need to be skipped, even if you feel you are racing the biological clock. The extra time is sometimes necessary to allow the ovaries to recover their optimal level of responsiveness. The skipped cycle can be used for additional testing (if indicated) or to discuss the strategy for the next cycle.

The two significant potential complications resulting from the use of gonadotropin stimulation are multiple gestation and ovarian hyperstimulation syndrome.

Multiple gestation
Multiple gestations (i.e. multiple pregnancies) occur because multiple eggs may be released and fertilized. However, it is the release of multiple eggs that increases the pregnancy rate for many couples. Thus, the risk of a multiple gestation is a necessary part of successful therapy. In general the risk of twins is about 20% - 25% per cycle, triplets about 5% per cycle, and quadruplets or more are extremely uncommon. If a multiple gestation occurs, selective reduction of one or more embryos can be performed at 12-13 weeks of pregnancy. Although this procedure is usually safely done under careful ultrasound guidance, there is about a 5% risk of miscarrying the remaining embryos.

Ovarian hyperstimulation syndrome
The second complication is the possibility of developing ovarian hyperstimulation syndrome, although this is uncommon with careful monitoring of follicle development. The symptoms of hyperstimulation begin about a week after ovulation. The ovaries become enlarged and tender, accompanied by abdominal bloating and fluid retention. Mild cases last about a week and usually respond to hydration and careful monitoring. Severe hyperstimulation occurs in 1% of cycles and may require hospitalization to ensure proper treatment. Rare cases of serious medical problems such as blood clots and stroke have been reported with ovarian hyperstimulation syndrome.

Concerns have been raised about the use of these drugs and ovarian cancer risks later in life. Current research indicates that the risk from these medications is either very low or non-existent, and long-term studies are ongoing. For reasons as yet undetermined, women who do not have children in their lifetime are at somewhat higher risk of developing ovarian cancer than those who do. This fact may be part of the reason for earlier concerns about fertility drugs. The important question is whether fertility drugs further increase one’s risk of cancers, and the answers thus far suggest that there is no such increase. Of note, studies to date show no increased risk of birth defects in children conceived with gonadotropin therapy.